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@ARTICLE{Andrzejak:164003,
      author       = {Andrzejak, Ewa Izabella and Rabinovitch, Eshed and Kreye,
                      Jakob and Prüss, Harald and Rosenmund, Christian and Ziv,
                      Noam E and Garner, Craig Curtis and Ackermann, Frauke},
      title        = {{P}atient-{D}erived {A}nti-{NMDAR} {A}ntibody {D}isinhibits
                      {C}ortical {N}euronal {N}etworks through {D}ysfunction of
                      {I}nhibitory {N}euron {O}utput.},
      journal      = {The journal of neuroscience},
      volume       = {42},
      number       = {15},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {DZNE-2022-00672},
      pages        = {3253-3270},
      year         = {2022},
      note         = {(CC BY)},
      abstract     = {Anti-NMDA receptor (NMDAR) encephalitis is a severe
                      neuropsychiatric disorder associated with autoantibodies
                      against NMDARs, which cause a variety of symptoms from
                      prominent psychiatric and cognitive manifestations to
                      seizures and autonomic instability. Previous studies mainly
                      focused on hippocampal effects of these autoantibodies,
                      helping to explain mechanistic causes for cognitive
                      impairment. However, antibodies' effects on higher cortical
                      network function, where they could contribute to psychosis
                      and/or seizures, have not been explored in detail until now.
                      Here, we employed a patient-derived monoclonal antibody
                      targeting the NR1 subunit of NMDAR and tested its effects on
                      in vitro cultures of rodent cortical neurons, using imaging
                      and electrophysiological techniques. We report that this
                      hNR1 antibody drives cortical networks to a hyperexcitable
                      state and disrupts mechanisms stabilizing network activity
                      such as Npas4 signaling. Network hyperactivity is in part a
                      result of a reduced synaptic output of inhibitory neurons,
                      as indicated by a decreased inhibitory drive and levels of
                      presynaptic inhibitory proteins, specifically in
                      inhibitory-to-excitatory neuron synapses. Importantly, on a
                      single-cell level hNR1 antibody selectively impairs
                      NMDAR-mediated currents and synaptic transmission of
                      cortical inhibitory neurons, yet has no effect on excitatory
                      neurons, which contrasts with its effects on hippocampal
                      neurons. Together, these findings provide a novel,
                      cortex-specific mechanism of antibody-induced neuronal
                      hyperexcitability, highlighting regional specificity
                      underlying the pathology of autoimmune
                      encephalitis.SIGNIFICANCE STATEMENT It is increasingly
                      appreciated that the inadvertent activation of the immune
                      system within CNS can underlie pathogenesis of
                      neuropsychiatric disorders. Although the exact mechanisms
                      remain elusive, autoantibodies derived from patients with
                      autoimmune encephalitis pose a unique tool to study
                      pathogenesis of neuropsychiatric states. Our analysis
                      reveals that autoantibody against the NMDA receptor (NMDAR)
                      has a distinct mechanism of action in the cortex, where it
                      impairs function of inhibitory neurons leading to increased
                      cortical network excitability, in contrast to previously
                      described hippocampal synaptic mechanisms of information
                      encoding, highlighting brain regional specificity. Notably,
                      similar mechanism of NMDAR-mediated inhibitory hypofunction
                      leading to cortical disinhibition has been suggested to
                      underlie pathology of schizophrenia, hence our data provide
                      new evidence for common mechanisms underlying
                      neuropsychiatric disorders.},
      keywords     = {Autoantibodies: metabolism / Encephalitis / Hashimoto
                      Disease / Humans / Neurons: physiology / Receptors,
                      N-Methyl-D-Aspartate: metabolism / Seizures: metabolism /
                      NMDAR (Other) / autoantibodies (Other) / autoimmune
                      encephalitis (Other) / cortical interneurons (Other) /
                      network excitability (Other) / Autoantibodies (NLM
                      Chemicals) / Receptors, N-Methyl-D-Aspartate (NLM
                      Chemicals)},
      cin          = {AG Garner / AG Prüß / AG Ackermann},
      ddc          = {610},
      cid          = {I:(DE-2719)1810001 / I:(DE-2719)1810003 /
                      I:(DE-2719)1813004},
      pnm          = {351 - Brain Function (POF4-351) / 353 - Clinical and Health
                      Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35241491},
      pmc          = {pmc:PMC8994542},
      doi          = {10.1523/JNEUROSCI.1689-21.2022},
      url          = {https://pub.dzne.de/record/164003},
}